This report describes intellectual disability, autosomal dominant 21, which shows dominant inheritance. The human gene implicated in this disease is CTCF, a versatile insulator and transcriptional regulator. There is a single high-ranking ortholog of CTCF in Drosophila, CTCF. Several alleles have been generated for CTCF, including hypomorphic alleles, RNAi targeting constructs, and alleles generated by insertional mutagenesis.
The human gene CTCF has not been introduced into flies.
Although overexpression or reduction of CTCF does not change neuromuscular junction anatomy greatly, both manipulations of CTCF levels impairs the flies' climbing ability, especially when CTCF is overexpressed in glia or motorneurons. A hypomorphic mutant of CTCF has impaired memory (both short- and long-term) and learning, as shown in a courtship conditioning assay.
[updated Jan 2020 by FlyBase; FBrf0222196]
Intellectual disability is characterized by impairments in intellectual functioning and adaptive behavior; symptoms must be present before a child becomes 18 years old (http://medical-dictionary.thefreedictionary.com/mental+retardation; 2016.01.19).
Intellectual disability can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by cognitive impairment without additional features (Basel-Vanagaite, 2008; DOI: 10.1002/9780470015902.a0021454).
[INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21; MRD21](https://omim.org/entry/615502)
[CCCTC-BINDING FACTOR; CTCF](https://omim.org/entry/604167)
All but one (due to young age) of the 36 affected individuals with intragenic CTCF aberrations classified as pathogenic or likely pathogenic presented with developmental delay and/or ID. The clinical spectrum of other phenotypes (cognitive impairment, walking age, age of first words, microcephaly, behavioral anomalies, cardiac defects, cleft palate, hearing or vision impairment) was highly variable. (Adapted from Konrad et al. 2019, FBrf0244177.)
Individuals with mutations in CTCF have symptoms including intellectual disability and microcephaly. [from MIM:615502, 2020.01.22]
Mental retardation-21 (MRD21) is caused by heterozygous mutation in the CTCF gene (604167) on chromosome 16q22. [from MIM:615502, 2020.01.22]
The identified aberrations in CTCF include two large deletions in 16q22.1, encompassing CTCF plus 26 or 43 neighboring genes, respectively. In addition, the following variants were identified: six frameshifting variants (including a deletion of exon 8); two nonsense variants; two variants in the splice acceptor site of exon 4, for one of which in-frame deletion of exon 4 was demonstrated; and 20 different missense variants. (Adapted from Konrad et al. 2019, FBrf0244177.)
CCCTC-binding factor (CTCF) is an important chromatin organizer involved in a range of gene regulation processes. When bound to insulator elements, CTCF can prevent spreading of inactive heterochromatin into neighboring regions and shield particular gene promoters from enhancer function. This enhancer blocking by CTCF might be methylation sensitive. CTCF is involved in maintaining three-dimensional chromatin structure, imprinting, X inactivation, and nucleosome positioning. (From Gregor et al. 2013 and references therein, pubmed:23746550.)
Transcriptional insulators are DNA elements that set boundaries on the actions of enhancer and silencer elements and thereby organize the eukaryotic genome into regulatory domains (Kuhn and Geyer, 2003, pubmed:12787766). All vertebrate insulators appear to use the versatile CTCF protein. CTCF uses various combinations of its 11 zinc fingers to recognize a variety of unrelated DNA sequences. Once bound to DNA, CTCF can function as a transcriptional insulator, repressor, or activator, depending on the context of the binding site (Jeong and Pfeifer, 2004, pubmed:15454938). [from MIM:604167, 2020.01.22]
One to one: 1 human gene to 1 Drosophila gene.
Single, high-ranking ortholog of human CTCF.
